Letters in Drug Design & Discovery, Volume 2, No. 5, 2005
Contents
Symmetrical Derivatives with
Nitrogenated Functions as Cytotoxic Agents and Apoptosis Inducers Pp.341-354
Carmen Sanmartin, Elena Ardaiz, Lucia Cordeu, Elena Cubedo, Jesus Garcia-Foncillas, Maria Font and Juan Antonio Palop
[Abstract]
Investigation of Tubulin
Polymerizing Agents: Synthesis of Substituted Cyclooctatrienes as a Possible
Taxoid Framework
Pp.355-363
A. Zand, P. Wagner, J. Song and J. Tischler
[Abstract]
Identification of Sanguinarine as
a Novel HIV Protease Inhibitor from High- Throughput Screening of 2,000 Drugs
and Natural Products with a Cell- Based Assay Pp.364-371
Ting-Jen Cheng, David S. Goodsell and Chen-Chen Kan
[Abstract]
Natural Endocannabinoid
Derivatives as Templates for the Development of FAAH Inhibitors Pp.372-376
Enrico Dainese and Mauro Maccarrone
[Abstract]
Indirubin-3'-Aminooxy-Acetate
Inhibits Glycogen Phosphorylase by Binding at the Inhibitor and the Allosteric
Site. Broad Specificities of the Two Sites Pp.377-390
Magda N. Kosmopoulo, Demetres D. Leonidas, Evangelia D.
Chrysina, Gerhard Eisenbrand and Nikos G. Oikonomakos
[Abstract]
New Perspectives in the
Modulation of the Eicosanoid Cascade in Inflammation Pp.391-402
J. Claria and M. Lopez-Parra
[Abstract]
Experimental Mouse Models of
Thrombosis Optimized for Drug Discovery and Development Pp.403-411
X. Wang
[Abstract]
M2000, Foundation of a New
Generation Among NSAIDs Pp.412-423
A. Mirshafiey, B. Rehm, S. Cuzzocrea, H. Matsuo, E. Mazzon,
S. Nakane, C-S. Koh and S. Miyoshi
[Abstract]
Aromatic Polycationic Molecules
with Restricted Conformations: An Alternative Approach to Antiherpes Agents Pp.424-427
Andrew Tsotinis, Margarita Vlachou, Andreas Eleutheriades,
Peter J. Garratt, Ashley J. Ibbett, Yiu-Fai Ng, Christophe Pannecouque, Myriam
Witvrouw and Erik De Clercq
[Abstract]
Abstracts
[Back to top]
Symmetrical Derivatives with Nitrogenated
Functions as Cytotoxic Agents and Apoptosis Inducers
Carmen Sanmartin, Elena Ardaiz, Lucia Cordeu, Elena Cubedo,
Jesus Garcia-Foncillas, Maria Font and Juan Antonio Palop
The synthesis and some pharmacological properties of new symmetrical
compounds are described. The cytotoxicity, apoptosis induction and caspase-3
activation of the synthesized compounds have been evaluated against three human
cancer cell lines. Compounds that showed cytotoxic activity were tested as
proapoptotic and caspase-3 activators. Some of the compounds showed interesting
values as apoptosis inducers and caused a notable increase in caspase-3 levels.
[Back to top]
Investigation of Tubulin Polymerizing
Agents: Synthesis of Substituted Cyclooctatrienes as a Possible Taxoid Framework
A. Zand, P. Wagner, J. Song and J. Tischler
The taxane family of compounds has proven to be synthetically challenging
targets. Using a novel [2+2] photocycloaddition reaction, several substituted
cyclooctatrienes were synthesized and tested for tubulin polymerization
activity. Elaboration of this methodology could allow the synthesis of a
modified taxoid scaffold thereby permitting the efficient synthesis of
paclitaxel analogs.
[Back to top]
Identification of Sanguinarine as
a Novel HIV Protease Inhibitor from High- Throughput Screening of 2,000 Drugs
and Natural Products with a Cell- Based Assay
Ting-Jen Cheng, David S. Goodsell and Chen-Chen Kan
We identified a non-peptidomimetic HIV protease inhibitor sanguinarine
through screening a small compound library with a high-throughput E. coli-based
assay. In vitro, sanguinarine inhibits the HIV protease with an IC50
of around 13 µM. Based on docking results, binding modes of sanguinarine to the
HIV protease are proposed.
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Natural Endocannabinoid Derivatives
as Templates for the Development of FAAH Inhibitors
Enrico Dainese and Mauro
Maccarrone
The endogenous cannabinoids (endocannabinoids) are amides, esters and
ethers of long chain polyunsaturated fatty acids. These lipids are bioactive
signaling molecules that show diverse cellular and physiological effects and
play various roles both in the central nervous system and in the periphery. The
discovery of N-arachidonoylethanolamine (anandamide, AEA) and of the
enzyme that terminates its signaling, i.e. fatty acid amide hydrolase (FAAH),
have inspired pharmacological strategies to augment endocannabinoid tone and
biological activity through inhibition of FAAH. Here we discuss the role of
natural endocannabinoid derivatives, like the hydroxy-anandamides (OH-AEAs)
generated from AEA via lipoxygenase activity, as powerful inhibitors of FAAH.
We propose that these compounds, by reversibly inhibiting FAAH, may control in
vivo the endocannabinoid tone. We discuss also the potential value of
OH-AEAs as templates for the development of next-generation therapeutics that
act at specific sites of FAAH.
[Back to top]
Indirubin-3'-Aminooxy-Acetate Inhibits
Glycogen Phosphorylase by Binding at the Inhibitor and the Allosteric Site.
Broad Specificities of the Two Sites
Magda N. Kosmopoulo, Demetres
D. Leonidas, Evangelia D. Chrysina, Gerhard Eisenbrand and Nikos G. Oikonomakos
The binding of the indirubin analogue indirubin-3'-aminooxy-acetate
(E243) to glycogen phosphorylase (GP) has been studied by kinetic and
crystallographic experiments. E243 was shown to be a competitive inhibitor of
GPb with respect to both Glc-1-P and AMP (Ki values of 21 ± 7 mM and 16 ± 3 mM,
respectively). The crystal structure of the GPb-E243 complex determined at 1.9
Å resolution showed one ligand molecule bound at the inhibitor site, mainly by
intercalating between the two aromatic side chains of Phe285 and Tyr613. In
addition, two E243 molecules, Mol 1 and Mol 2, were bound at the allosteric
activator AMP binding site and a new sub-site in the vicinity of the allosteric
site, respectively, with their indole-aminooxy-acetate rings inclined
approximately 40º. The binding mode of E243 to GPb inhibitor and allosteric
site is different from those of flavopiridol, AMP, Glc-6-P, W1807, and a potent
phenoxy-phthalate compound, previously described, illustrating how the enzyme
can accommodate a number of diverse chemical entities.
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New Perspectives in the Modulation
of the Eicosanoid Cascade in Inflammation
J. Claria and M. Lopez-Parra
Cyclooxygenase and 5-lipoxygenase pathways, which convert arachidonic
acid into prostaglandins and leukotrienes, respectively, are the two major
pro-inflammatory routes, whereas lipoxins, resolvins and neuroprotectins are
potent endogenous anti-inflammatory mediators. Modulation of these pathways is
key to control inflammation and to promote its resolution.
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Experimental Mouse Models of Thrombosis Optimized for Drug
Discovery and Development
X. Wang
Animal models of diseases are essential for drug discovery and
development. The availability of a large number of genetically-manipulated mice
renders considerable interest in drug discovery by means of experimental models
of disease. Ferric chloride-induced thrombosis is one of the most commonly used
experimental models of thrombosis in mice. This review provides examples of
optimizing this arterial thrombosis model for target validation and drug
discovery in mice.
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M2000, Foundation of a New Generation Among NSAIDs
A. Mirshafiey, B. Rehm, S.
Cuzzocrea, H. Matsuo, E. Mazzon, S. Nakane, C-S. Koh and S. Miyoshi
This investigation was planned to assess the therapeutic efficacy of a novel
designed nonsteroidal anti-inflammatory drug, M2000 (ß- D- mannuronic acid) in
experimental models of rheumatoid arthritis, multiple sclerosis,
glomerulonephritis, and nephrotic syndrome.
The anti-inflammatory property of M2000 was tested in Adjuvant-induced
arthritis (AIA) by intraperitoneal (i.p.) administration of 40 mg/Kg/day M2000
and compared with indomethacin. The immunosuppressive effect of M2000 was
evaluated using experimental model of multiple sclerosis, (Experimental
autoimmune encephalomyelitis “EAE”). Its therapeutic potency on kidney diseases
was studied using experimental models of nephrosis ( Adriamycin-induced
nephropathy) and immune complex glomerulonephritis ( bovine serum albumin
nephritis) by i.p. injection of M2000( 30mg/Kg/day) and compared with
Piroxicam. Biocompatibility and pharmacotoxicology assessment of M2000 was
carried out using WEHI-164 cell line, zymography method and determining the
serum and urine parameters in healthy controls receiving M2000. Results showed
that i.p. administration of M2000 to arthritic rats significantly reduced paw
edema, and anti-inflammatory effect of tested drug was equivalent to that
observed after treatment by Indomethacin. Immunosuppressive property of M2000
could significantly reduce clinical signs and histological erosions in treated
Lewis rats compared with non-treated controls in EAE model, as well as lymph
node cells proliferative assay in EAE confirmed immunosuppressive efficacy of
tested drug. Our data in experimental model of immune complex
glomerulonephritis and experimental nephrosis using Sprague-Dawley rats showed
that i.p. administration of M2000 could significantly decrease the urinary
protein excretion, blood urea nitrogen (BUN), serum creatinine and plasma
concentration of cholesterol, as well as glomerular hypercellularity, PMN
infiltration and cast formation in histological assessment of kidney in treated
rats by M2000 compared with non-treated animals. Our findings using
Fibrosarcoma (WEHI, 164) cell line revealed that tested drug has an inhibitory
effect on Matrix Metalloproteinase 2 activity compared to Dexamethasone,
Piroxicam and Diclofenac. Pharmacotoxicology study using animal models and in
vitro examination showed that M2000 is the safest anti-inflammatory and
immunosuppressive drug with the greatest tolerability in comparison with
Dexamethasone and tested conventional NSAIDs. Additionally, M2000 had no
ulcerogenic effect on rat stomach and had no influence on the body temperature
of normothermic rats at its anti-inflammatory dose range.
Our data indicate that M2000 as a new anti-inflammatory drug with
immunosuppressive property and greatest tolerability not only has no
gastro-nephrotoxicity, but it is the first novel designed NSAID with lowest
molecular weight and therapeutic effects on glomerulonephritis and nephrosis
due to which it could be strongly recommended in an extensive scale as a safest
drug for decreasing the anti-inflammatory reactions.
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Aromatic Polycationic Molecules with Restricted Conformations:
An Alternative Approach to Antiherpes Agents
Andrew Tsotinis, Margarita Vlachou, Andreas Eleutheriades,
Peter J. Garratt, Ashley J. Ibbett, Yiu-Fai Ng, Christophe Pannecouque, Myriam
Witvrouw and Erik De Clercq
A series of aromatic polycationic molecules were synthesised and tested
as potential non-classical antiherpes agents. Analogue (4) had a high potency
in all four of the HSV cell lines used and is far more potent than ribavirin.
The fact that none of the new compounds show any selectivity for HSV-2 over
HSV-1 may imply that there is no intervention of a HSV-2 glycoprotein C (gC)
dependent pathway.